The findings may be useful in designing optimal tools for measuring response to treatment in FAP, researchers said.
The study, “Mnis+7 And Lower Limb Function In Inotersen Treatment Of Hattr,” was published in the journal Muscle & Nerve, and was funded by Akcea Therapeutics, a subsidiary of Ionis Pharmaceuticals, which markets Tegsedi.
FAP, also called hereditary transthyretin amyloidosis (hATTR), is characterized by the buildup of the protein transthyretin (TTR). Tegsedi is an approved treatment for FAP that works by blocking the production of TTR protein.
Tegsedi was approved to treat stage 1 or 2 polyneuropathy in adults with FAP in Europe, the U.S., and other countries, and recently was approved for reimbursement in Austria, Portugal, Spain, and Italy.
The efficacy of Tegsedi was demonstrated in the Ionis-funded NEURO-TTR Phase 2/3 trial (NCT01737398). Results demonstrated that, relative to a placebo, treatment with Tegsedi significantly reduced TTR protein levels, improved quality of life, and reduced neurological dysfunction, as assessed with the modified Neuropathy Impairment Score +7 (mNIS+7).
This consists of both polyneuropathy signs (e.g., muscle weakness, reflex impairments, sensation loss) and neurophysiological tests, such as measuring nerve conduction or how heart rate changes in response to deep breathing.
While previous analyses of NEURO-TTR data assessed mNIS+7 scores collectively, the team conducting the new study analyzed the individual components of this assessment to better understand the effects of Tegsedi.
The researchers also analyzed lower limb function using a test in which a neurologist evaluates individuals’ abilities to walk on their toes, walk on their heels, and stand from a kneeling position. Scores can range from zero (no impairment) to six (bilateral impairment in all three components).
A total of 165 patients were included — 106 treated with Tegsedi and 59 given a placebo. The two groups were similar in terms of mean age (about 59) and time since diagnosis, which was nearly 40 months. In both groups, about two-thirds of participants had stage one disease; the remainder had stage two disease.
Assessments were conducted at the start of the study, after 35 weeks (about eight months), and after 66 weeks (nearly 15 months).
Compared with placebo, Tegsedi treatment resulted in lack of progression of polyneuropathy, as reflected in mNIS+7 measurements of muscle strength, reflexes, and heat–pain sensation. Significant improvement also was seen in overall nerve conduction at week 66.
Upper limb reflexes, sensations of touch or pressure, and changes to heart beat in response to deep breathing were not significantly different between the Tegsedi and placebo groups.
The lack of significance may mean that some current components of the mNIS+7 tool are not suitable for measuring treatment benefits in FAP, the team suggested.
Changes in lower limb scores — both total scores and for each of the three individual components — were significantly lower (better) in the Tegsedi group than the placebo group.
When participants who started the study with greater impairment (score of five or six) were excluded from the analysis, significantly fewer patients on Tegsedi than on placebo experienced worsening motor function at week 66 (22.4% vs. 55.2%). Also, while none of the participants given a placebo experienced an improvement in total limb function, 8.4% of those given Tegsedi showed benefits at the end of treatment.
“The results of this analysis reinforce the beneficial effect of [Tegsedi] on slowing neuropathy progression in patients with hATTR polyneuropathy,” the team wrote.
Overall, the findings also indicate that assessing lower limb function could be used to detect treatment benefits in FAP. However, it is not without limitations: “A ceiling effect was observed with the lower limb function assessment, as roughly 40% of patients already had an abnormality in each lower limb function component at baseline. Thus, it may not be a strong tool to use in assessing patients with a more advanced or severe disease,” added the investigators, three of whom are employees of Akcea or Ionis.
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